7.Tumor Angiogenesis

1. Why tumors need angiogenesis

Tumors cannot grow beyond ~1–2 mm thickness without new blood vessels because:

• oxygen + nutrients delivered by diffusion only reach this distance
• waste removal becomes inefficient beyond this limit

Without vascular support, tumors remain tiny and dormant.

Neoangiogenesis = formation of new blood vessels from existing vasculature, induced by tumor signals.

Benefits of angiogenesis for tumors

• ↑ oxygen and nutrient delivery
• ↑ waste removal
• endothelial cells secrete growth factors (PDGF, IGFs) that stimulate proliferation
• new vessels are abnormal + leaky, allowing tumor cells to enter bloodstream → metastasis risk ↑

2. Angiogenesis regulation + the “angiogenic switch”

Tumor angiogenesis depends on the balance between:

Pro-angiogenic factors (“GO” signals)

• VEGF
• PDGF
• IGF
• bFGF

Anti-angiogenic factors (“STOP” signals)

• Thrombospondin-1
• Angiostatin
• Endostatin

Many tumors begin as non-angiogenic and remain small for years until the angiogenic switch occurs, allowing expansion beyond dormancy.

Switch triggers may arise from tumor cells themselves, from macrophages, or fibroblasts in tumor stroma.

3. Proteases and the microenvironment

Proteases in the tumor microenvironment act like molecular scissors with a dual function:

1. Release stored pro-angiogenic bFGF from the ECM → increases angiogenesis
2. Generate anti-angiogenic molecules through cleavage:
• Angiostatin cut from plasminogen
• Endostatin cut from collagen

Thus, ECM remodeling influences angiogenic balance dynamically.

4. Hypoxia, genetic pathways, and pro-angiogenic signaling

Hypoxia-driven angiogenesis

Low oxygen:

• stabilizes HIF-1α
• increases transcription of VEGF + other pro-angiogenic cytokines
• establishes chemotactic gradient → vessels grow toward tumor

Genetic alterations that increase angiogenesis

• Loss of p53:
• ↓ thrombospondin-1 (anti-angiogenic brake)
• ↑ VEGF
• Activation/mutation of RAS or MYC:
• drives VEGF overexpression

Clinical finding:

• elevated VEGF detectable in the blood and urine of many cancer patients

5. Anti-angiogenic therapy

Goal = neutralize key pro-angiogenic signals.

Main approved drug:

• Bevacizumab — monoclonal antibody against VEGF

Therapeutic outcomes:

• slows tumor growth temporarily
• prolongs survival modestly
• does not cure cancer

Limitations:

• tumors develop escape pathways independent of VEGF
• angiogenesis inhibition targeting endothelial support is insufficient long-term

FULL SUMMARY TABLE

Micro-glossary (plain language)

• VEGF: strongest “grow blood vessels” signal
• bFGF/PDGF/IGF: supporting growth signals
• Thrombospondin-1: built-in brake from p53
• Angiostatin/Endostatin: brakes generated from ECM cleavage
• Hypoxia/HIF-1α: low oxygen trigger for VEGF production
• Angiogenic switch: transition from dormant tumor to vascular tumor

🧠 EXAM REFLEX BLOCK — Tumor Angiogenesis (High-Yield, Examiner-Safe)

Core trigger

• Tumors cannot grow beyond ~1–2 mm without neovascularization because diffusion of O₂/nutrients and waste removal are limited.

Definition lock

• Neoangiogenesis = formation of new blood vessels from pre-existing vasculature, driven by tumor-derived signals.

Why angiogenesis helps tumors

• Enables continued growth beyond dormancy
• Improves oxygen + nutrient delivery
• Improves waste removal
• Produces abnormal, leaky vessels → facilitates intravasation and metastasis

Angiogenic switch (key concept)

• Tumors remain non-angiogenic and dormant for years
• Switch occurs when pro-angiogenic signals outweigh anti-angiogenic brakes
• Switch signals can arise from:
• Tumor cells
• Tumor-associated macrophages
• Cancer-associated fibroblasts

Pro-angiogenic factors (GO)

• VEGF (most important)
• PDGF
• IGF
• bFGF

Anti-angiogenic factors (STOP)

• Thrombospondin-1
• Angiostatin
• Endostatin

Proteases — dual examiner favorite

• ECM proteases:
• Release bFGF stored in ECM → ↑ angiogenesis
• also Generate angiogenesis inhibitors:
• Angiostatin from plasminogen
• Endostatin from collagen
• ⇒ ECM remodeling dynamically controls angiogenic balance

Hypoxia pathway (very high yield)

• Tumor hypoxia → HIF-1α stabilization
• HIF-1α → ↑ VEGF transcription
• Creates chemotactic gradient → vessels grow toward tumor

Genetic alterations that ↑ angiogenesis

• Loss of p53:
• ↓ Thrombospondin-1 (loss of brake)
• ↑ VEGF
• Activation of RAS or MYC:
• Direct ↑ VEGF expression

Clinical correlation

• VEGF levels elevated in serum and urine of many cancer patients

Therapeutic reflex

• Anti-angiogenic therapy target = VEGF
• Bevacizumab (anti-VEGF monoclonal antibody):
• Slows tumor growth
• Modest survival benefit
• Does NOT cure cancer

Why therapy fails long-term (exam trap)

• Tumors activate VEGF-independent angiogenic pathways
• Targeting endothelial support alone is insufficient

🧩 One-line exam memory hook

Tumors stay ≤2 mm until hypoxia → HIF-1α → VEGF → leaky vessels → growth + metastasis; p53 loss removes brakes, RAS/MYC press accelerator.